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J Clin Invest. 2017 Jun 30;127(7):2689-2696. doi: 10.1172/JCI93289. Epub 2017 Jun 19.

Clonal expansion of genome-intact HIV-1 in functionally polarized Th1 CD4+ T cells.

Author information

1
Infectious Disease Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
2
Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, USA.
3
HIV Pathogenesis Programme, Doris Duke Medical Research Institute, and.
4
KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.
5
Max Planck Institute for Infection Biology, Berlin, Germany.
6
Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
7
Infectious Disease Division, Massachusetts General Hospital, Boston, Massachusetts, USA.

Abstract

HIV-1 causes a chronic, incurable disease due to its persistence in CD4+ T cells that contain replication-competent provirus, but exhibit little or no active viral gene expression and effectively resist combination antiretroviral therapy (cART). These latently infected T cells represent an extremely small proportion of all circulating CD4+ T cells but possess a remarkable long-term stability and typically persist throughout life, for reasons that are not fully understood. Here we performed massive single-genome, near-full-length next-generation sequencing of HIV-1 DNA derived from unfractionated peripheral blood mononuclear cells, ex vivo-isolated CD4+ T cells, and subsets of functionally polarized memory CD4+ T cells. This approach identified multiple sets of independent, near-full-length proviral sequences from cART-treated individuals that were completely identical, consistent with clonal expansion of CD4+ T cells harboring intact HIV-1. Intact, near-full-genome HIV-1 DNA sequences that were derived from such clonally expanded CD4+ T cells constituted 62% of all analyzed genome-intact sequences in memory CD4 T cells, were preferentially observed in Th1-polarized cells, were longitudinally detected over a duration of up to 5 years, and were fully replication- and infection-competent. Together, these data suggest that clonal proliferation of Th1-polarized CD4+ T cells encoding for intact HIV-1 represents a driving force for stabilizing the pool of latently infected CD4+ T cells.

PMID:
28628034
PMCID:
PMC5490740
DOI:
10.1172/JCI93289
[Indexed for MEDLINE]
Free PMC Article

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